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Breathing New Life Into Lung Cancer Research

The story of cancer was long seen as a single narrative: a cell acquires genetic mutations, starts to divide uncontrollably and then spreads.

But in recent years, this tale has become more complex. Scientists are increasingly aware that a tumor’s microenvironment — its surrounding healthy cells, including fibroblasts that form connective tissues, as well as blood vessels and immune cells — are more than just innocent bystanders, they actively contribute to the developing tumor and can play a role in encouraging its growth or keeping it at bay. 

To better understand the role of the tumor microenvironment, scientists have been working in recent years to develop cell culturing techniques that can grow cells in 3-D using scaffolding matrices. The traditional 2-D models that grow cancer cells in a flat, plastic dish do not capture this biological complexity. While several 3-D models have been widely used in the field, scientists, until recently, were unable to create a 3-D model for a hard-to-treat subtype of lung cancer known as squamous cell carcinoma. 

This discovery gave us the unique opportunity to study how a tumor cell’s genetic mutations as well as changes in the tumor microenvironment could affect tissue architecture and promote or inhibit the development of lung cancer.

Dr. Shuang Chen

But now a team of Pfizer scientists have developed a novel 3-D model for lung squamous carcinoma (LUSC), which has led to important insights into how these cancer cells behave and could lead to potential new treatments. “We discovered that a unique lung cancer cell line was capable of developing 3-D structures in a dish similar to lung tissue organization found inside the body,” says Dr. Kenneth Geles, a Director in the Targeted Therapeutics Discovery group, Oncology R&D at Pfizer’s Pearl River, N.Y. research site. “It’s a big leap forward because modeling human lung tumor architecture in 3-D had previously been difficult to capture outside the body,” adds Geles, who with his team, recently authored a study on this pioneering research that will be published in the Proceedings of the National Academy of Sciences

A “living” scaffold

When cancer cells are grown in 2-D conditions they multiply uncontrollably but only grow flat. But if cells are cultivated on a “biological scaffold,” as Geles and his team did, they form 3-D structures that resemble tissues found in the human body. To create their model, Pfizer scientists took cell samples from lung cancer patients, growing them in a scaffold made of a jelly-like substance that contained a mixture of proteins, intended to mimic the typical microenvironment seen in tumors. “It not only provided structural support, but since it supplies biological instructions, it dictates information to the cancer cells, such as to divide, to self-organize or to lay dormant,” says Dr. Shuang Chen, a Postdoctoral fellow and lead author of the study who is based at Pfizer’s Pearl River, N.Y. research site. 

An image of a 3-D lung cancer acinar-like structure composed of a monolayer of cells surrounding a hollow cavity. Janet Gruzas, Kenneth Geles

Most of the cells grown in the scaffold followed the typical pattern of growing into disorganized clusters. But surprisingly, in one of their experimental cell culture models, the cells started to revert back to a more organized state, resembling a round, hollow cluster of cells known as acinus similar to a lung air sac. Despite their normal appearance, these cells grew continuously and were capable of forming new tumors. 

By including the tumor-microenvironment components, Chen and Geles observed how these cancer cells have a high degree of plasticity—in other words, that they can morph into different states that affect their ability to survive under different conditions and multiply. “This discovery gave us the unique opportunity to study how a tumor cell’s genetic mutations as well as changes in the tumor microenvironment could affect tissue architecture and promote or inhibit the development of lung cancer,” says Chen. 

When fibroblasts were added to the 3-D culture, the lung cancer acinar-like structures became more aggressive and invaded the scaffolding matrix. Shuang Chen

Scientists will need much more research to understand what exact instructions are provided by the “living scaffold” that can reverse the aberrant behavior of the cancer cells. However, says Geles, “We’ve used this model to show that by turning on/off specific signaling pathways in the cancer cell, we could further change their behavior to grow more disorganized, thus allowing us to identify genes controlling each of these cell states.” 

The team of researchers were also able to identify additional components in the tumor microenvironment that had the opposite effect and made the cancer cells more dangerous. When scientists added cancer-associated fibroblasts (CAFs) to the 3-D model, the tumor cells within the acinar-like structures grew faster and became aggressive. This complex 3D culture system now enables the scientists to screen for factors and anti-cancer agents that can prevent or halt this invasive behavior. 

“Our data suggest that instead of solely targeting tumor cells in cancer therapy, targeting the dynamic and reciprocal interactions between tumor cells and the microenvironment could present the basis of new and more effective treatment options for patients,” says Chen. 

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